We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-to-background ratio and information content. The Omni-ATAC protocol generates chromatin accessibility profiles from archival frozen tissue samples and 50-μm sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies.

Author contributions L.M.M. and S.K. conceived the project and designed the experiments. L.M.M., M.L., E.G. and R.M. curated patient samples. S.K. led data production and performed the experiments together with A.S.K., A.M. and L.M.M. G.X.Y.Z. provided healthy bone marrow and peripheral blood CITE-seq data. S.K. analyzed the scADT-seq data with contribution from B.P. M.R.C. performed data analysis. J.M.G. conceived the analytical workflows and performed the data analysis for scATAC-seq and scRNA-seq supervised by H.Y.C. and

A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here, we collected ATAC-seq and RNA-seq data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulationresponsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Use of allele-specific read-mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need for characterization of effects of genetic variation in stimulated cells.

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We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-tobackground ratio and information content. The Omni-ATAC protocol enables chromatin accessibility profiling from archival frozen tissue samples and 50 µm sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies.